Peripartum nevirapine (NVP) is an important and effective intervention for perinatal HIV prevention in resource-constrained settings. This simple regimen substantially reduces mother-to-child transmission of the virus when used alone or in combination with other antiretroviral drugs. Numerous studies, however, have demonstrated significant viral drug resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs (of which NVP is a part) in the weeks following ingestion of the single maternal dose. Although these resistance mutations appear transient by standard assays, resistant virus could become latent, and only later compromise treatment response when women start antiretroviral therapy. In Dr. Chi's original IRSDA, he conducted a randomized trial of adjuvant single-dose tenofovir (TDF, SOOmg) / emtricitabine (FTC, 200mg) to reduce postpartum NNRTI resistance. The intervention was associated with a 73% reduction in drug resistance at two weeks postpartum (RR = 0.27, 95%CI = 0.11, 0.66) and a 53% reduction at six weeks (RR = 0.47, 95%CI = 0.29, 0.77). Although effective, in absolute terms, a significant proportion of women (12%) still developed NNRTI resistance with the intervention. This is concerning because peripartum NVP remains an integral part of PMTCT for the majority of HIV-infected women worldwide. For his IRSDA renewal, Dr. Chi proposes a follow-up clinical trial to investigate optimized dosing of the TDF/FTC regimen. He will compare the single-dose intrapartum TDF/FTC (SOOmg / 200mg) regimen with a two-dose regimen of TDF/FTC (GOOmg MOOmg), taken in labor and upon discharge from the delivery ward. Dr. Chi hypothesizes that this enhanced adjuvant regimen will significantly reduce postpartum NNRTI resistance at 6 weeks postpartum, from 12% to 3%. Alongside this primary project, Dr. Chi will continue to work closely with his mentors to solidify his expertise in obstetrics, HIV medicine, and international health. He will build proficiency in other research methodologies such as cost-effectiveness analysis, survey studies, and cohort analysis. The ultimate goal of this renewal will be Dr. Chi's development into an independently funded research scientist, so that he may continue to investigate important and relevant research questions for resource-constrained settings such as Zambia. PUBLIC HEALTH RELEVANCE: Although single-dose nevirapine is simple and effective for perinatal HIV prevention, its use can lead to the development of drug-resistant viral strains. In this grant, Dr. Chi is investigating a novel method to reduce the development of this drug resistance. If effective, this intervention could have an immediate impact in settings where single-dose nevirapine is used, and potentially improve the long-term health outcomes among HIV-infected women and their children.